Specific phosphorylation of αA-crystallin is required for the αA-crystallin-induced protection of astrocytes against staurosporine and C2-ceramide toxicity
Specific phosphorylation of αA-crystallin is required for the αA-crystallin-induced protection of astrocytes against staurosporine and C2-ceramide toxicity
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DOI：
10.1016/j.neuint.2012.02.031
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发表时间：
2012-05-01
影响因子：
4.2
通讯作者：
Reiser, Georg
中科院分区：
文献类型：
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作者：
Li, Rongyu;Zhu, Zhihui;Reiser, Georg
我们先前报道了α A-晶状体蛋白和蛋白酶活化受体参与保护星形胶质细胞免受C2-神经酰胺和星形孢菌素诱导的细胞死亡（Li等人，2009年）。在这里，我们研究了α A-晶状体蛋白介导的细胞保护的分子机制。我们发现，模拟特异性磷酸化α A-晶体蛋白的突变体的表达增加了星形胶质细胞的保护。然而，模拟α A-晶状体蛋白去磷酸化的突变体的表达导致保护的丧失。这些数据表明，在Ser 122和Ser 148的α A-晶体蛋白的磷酸化是保护所必需的。进一步探讨了α A-晶状体蛋白对星形胶质细胞的保护作用机制。应用p38和ERK的特异性抑制剂可通过α A-晶状体蛋白的过度表达消除星形胶质细胞的保护作用。因此，p38和ERK有助于通过α A-晶状体蛋白的保护过程。这与我们先前的结果相当，该结果表明p38和ERK调节蛋白酶激活受体2（PAR-2）/α B-晶状体蛋白介导的细胞保护。此外，我们发现PAR-2激活增加了α A-晶体蛋白的表达。因此，内源性α A-晶状体蛋白通过调节α A-晶状体蛋白的表达和/或磷酸化状态的机制保护星形胶质细胞。(C)2012爱思唯尔有限公司保留所有权利。
We previously reported that alpha A-crystallin and protease-activated receptor are involved in protection of astrocytes against C2-ceramide- and staurosporine-induced cell death (Li et al., 2009). Here, we investigated the molecular mechanism of alpha A-crystallin-mediated cytoprotection. We found that the expression of mutants mimicking specific phosphorylation of alpha A-crystallin increases the protection of astrocytes. However, the expression of mutants mimicking unphosphorylation of alpha A-crystallin results in loss of protection. These data revealed that the phosphorylation of alpha A-crystallin at Ser122 and Ser148 is required for protection. Furthermore, we explored the mechanism of cytoprotection of astrocytes by alpha A-crystallin. Application of specific inhibitors of p38 and ERK abrogates the protection of astrocytes by over-expression of alpha A-crystallin. Thus, p38 and ERK contribute to protective processes by alpha A-crystallin. This is comparable to our previous results which demonstrated that p38 and ERK regulated protease-activated receptor-2 (PAR-2)/alpha B-crystallin-mediated cytoprotection. Furthermore, we found that PAR-2 activation increases the expression of alpha A-crystallin. Thus, endogenous alpha A-crystallin protects astrocytes via mechanisms, which regulate the expression and/or phosphorylation status of alpha A-crystallin. (C) 2012 Elsevier Ltd. All rights reserved.